This application is a 371 of PCT/JP99/05826 filed on Oct. 22, 1999.
The present invention relates to vitamin D3 derivatives useful as pharmaceutical products or pharmaceutically permissible solvates thereof, treating agents using same and pharmaceutical compositions containing same. More particularly, the invention relates to 1xcex1-hydroxyvitamin D3 derivatives having neutrophilic infiltration-suppressing activity and antagonistic effect to vitamin D3 or pharmaceutically permissible solvates thereof, treating agents for inflammatory respiratory diseases and diseases attributable to the overactivity of vitamin D3 containing same as active ingredients and pharmaceutical compositions containing same.
An active vitamin D3 derivative has calcium absorption-stimulating activity in the small intestine, and activities such as the control of bone resorption and osteogenesis in the bones, and it is used as a treating agent for diseases caused by various kinds of calcium metabolism disorders. In recent years, immunoregulatory activity, cell proliferation inhibitory activity and cell differentiation inducting activity have been found besides these activities. For example, applications to a treating agent for malignant tumor (JP-A 57-149224 (hereinafter, JP-A means Japanese unexamined patent publication)), a treating agent for rheumatoid arthritis (JP-A 56-26820), an antiallergic agent (JP-A 63-107928, English Patent Publication No. 2260904 (GB 2260904-A)), a treating agent for psoriasis (JP-A 3-68009), a treating agent for diseases attributable to thromboxane A2 production (JP-A 5-294834), a treating agent for eczema and dermatitis (JP-A 7-291868), etc., are being studied.
Respiratory tract infection is a disease which is established when pathogens invade into the respiratory tract by getting over its infection preventing mechanisms, and the treatment is mainly based on the improvement of respiratory tract clearance by using a bronchodilator, an expectorant, etc. But, in the case of acute exacerbation with infection, the main treatment is the use of a strong antibacterial agent against phlogogenic bacteria. However, most underlying diseases constantly becomes worse when acute exacerbation is repeated. Further, current treatments, which depend on antibacterial agents in the extreme, are under reconsideration owing to the emergence of resistant bacteria such as MRSA.
Recently, the usefulness of a low-dose long administration of erythromycin for a chronic lower airway infectious disease has been reported, and it attracts medical attention. A chronic lower respiratory infectious disease is a generic name for bacterial infections observed in chronic bronchitis, diffuse panbronchiolitis, bronchiectasis, etc., (sometimes, it includes bronchial asthma, chronic pulmonary emphysema, tuberculosis sequela, etc., accompanied by infection). Although these are different in the name of disease, it is known that all of the diseases take common morbid states such as purulent sputum in large amount, fatigue dyspnea and hypoxemia. Regarding the working mechanism of erythromycin, it is estimated that erythromycin""s function does not based simply on its antibacterial activity, namely, erythromycin acts not on bacteria themselves, and it is understood that erythromycin acts rather on inflammatory cells which accumulate on the airway accompanying the bacteria, especially acts on neutrophils. That is, neutrophils are considered to infiltrate into tissues by the various kinds of stimulation caused by the infection to release protease as well as activated oxygen, and these substances cause epithelium damage, the trouble of ciliary movement and mucosa hypersecretion to exert a bad influence upon respiratory physiological effect, and erythromycin acts on these processes. Based on such consideration, a medicine, which suppresses the pulmonary tissue infiltration of neutrophils or suppresses the activity of neutrophils, can be useful as a treating agent for inflammatory dyspnea, for example, chronic lower airway infectious disease.
On the other hand, when the control of vitamin D production becomes abnormal due to diseases, etc. and the intracorporeal concentration increases to ex press physiological effect excessively, various diseases attributable to the excess of the vitamin D are developed. For example, it is known that, in sarcoidosis, vitamin D is excessively produce by a tumorigenic macrophage-like cell (J. Clinical Invest., 64, 218-225 (1979)), and as a result, hypercalcemia is developed. For the treatment of the disease, a glucocorticoid is mainly used, but the long term administration of a large amount of the glucocorticoid causes adverse reaction. On the other hand, vitamin D is known to exhibit its physiological effect via intracellular vitamin D receptors, and thereby a vitamin D3 antagonist, which is specific to the expression of effect via receptor, is supposed to be effective in order to suppress the excessively developed vitamin D activity.
Incidentally, an active vitamin D3 controls the amount of production of parathyroid hormone (henceforth, this may be referred to as PTH) in a living body, and the amount of production of PTH is lowered by the increase of the production of the active vitamin D3. Thereby, it is thought that the use of a vitamin D3 antagonist corrects the decrease of PTH production attributable to the increase of active vitamin D3 production, and further can accelerate the production of PTH. It is known that various diseases are caused by the decrease of PTH production, and one of the examples is hypoparathyroidism. The administration of PTH is considered to be ideal for the treatment of the disease; however, an orally administrable PTH preparation has not been developed yet. On the other hand, a vitamin D3 antagonist is orally administrable, and thereby, the antagonist is supposed to be useful as an ideal treating agent for hypoparathyroidism.
Further, there are reports that PTH has effects on the growth and the differentiation of a cartilage cell, and the biosynthesis of cartilaginous matrix (Cellular and Calcium, 16, 112-122 (1994), and Calcified Tissue International, 50, 61-66 (1992)), on an osteoblast growth stimulating activity (Endocrinology, 118, 2445-2449 (1986)), on a collagen biosynthesis stimulating activity (J. Clin. Invest., 83, 60-65 (1989)) and the like. These reports show that PTH can become effective treating agents for metabolic disorder of cartilage and metabolic disorder of bone, and actually, a clinical investigation on osteogenesis is progressing by using an intramuscular injection preparation. However, an intramuscular injection preparation has such problems that the half life is short, and that hyperostosis, which is supposedly related to a transient increase in the intracorporeal concentration of PTH, is caused. On the other hand, a vitamin D3 antagonist is orally administrable, and thereby it is supposed that the antagonist can solve these problems, and can be useful as an ideal treating agent for metabolic disorder of cartilage and that of bone.
Prior arts of the compound of the present invention are shown below.
The International Patent Publication WO95/33716 shows that compounds having an xcex1-methyl lactone structure or an xcex1-methylene lactone structure as the side chain of vitamin D3 have an osteogenesis stimulation activity. However, the compounds disclosed by the present invention do not include the above-mentioned compounds, and further there is no description nor suggestion regarding that the compounds described in the publication have a neutrophilic infiltration suppressing activity or an antagonistic effect to vitamin D3.
U.S. Patent Publication, U.S. Pat. No. 5,354,872 describes the method for the production of compounds having an xcex1-hydroxy lactone structure or an xcex1-hydroxy-xcex1-alkyl lactone structure as the side chain of vitamin D3; however, the compounds disclosed by the present invention do not include the above-mentioned compounds, and further there is no description nor suggestion regarding that the compounds described in the above-mentioned publication have a neutrophilic infiltration suppressing activity or an antagonistic effect to vitamin D3.
J. Org. Chem., 48, 4433-4436 (1983), U.S. Patent Publication, U.S. Pat. No. 5,604,257 and the like describe compounds having an xcex1-hydroxy-xcex1-methyl lactone structure as the side chain of vitamin D3, and the publication suggests an application as a treating agent for hypercalcemia, cancer, osteoporosis and the like. However, the compounds disclosed by the present invention do not include the above-mentioned compounds, and further there is neither description nor suggestion regarding that the compounds described in the above-mentioned literature and publication have a neutrophilic infiltration suppressing activity or an antagonistic effect to vitamin D3.
International Patent Publication WO95/33716 describes that compounds having a carboxyl group or an ester group as a substituent at the 25-position of the side chain of vitamin D3 have an osteogenesis stimulation activity. However, these compounds are clearly different from the compounds of the present invention having an amide group, an alkylcarbonyl group or a hydroxyalkyl group as a substituent at the 25-position of the side chain of vitamin D3, and further there is no description nor suggestion regarding that the compounds described in the publication have a neutrophilic infiltration suppressing activity or an antagonistic effect to vitamin D3.
International Patent Publication WO94/07853 describes that compounds having a carboxyl group, an ester group, an amide group, a thioester group or a cyano group as a substituent at the 25-position of vitamin D3 have a cell differentiation inducting activity. However, the compounds disclosed by the publication have such a carboxyl group, an ester group, an amide group, a thioester group or a cyano group, and at the same time, a carbonyl group, a chlorine atom, a fluorine atom, a trifluoromethyl group or an alkyl group as the substituents at the 25-position of vitamin D3, and they have a hydroxyl group or an alkoxy group at the 24-position, and further the bonding between the 22-position and the 23-position is a double bond. The compounds of the present invention have an amide group, an alkylcarbonyl group or a hydroxyalkyl group, and at the same time, a hydroxy group as the substituents at the 25-position, and the 24-position has no substituent, and the bonding between the 22-position and the 23-position is a single bond, and they are clearly different from the compounds described in the publication. Further, there is no description nor suggestion regarding that the compounds described in the publication have a neutrophilic infiltration suppressing activity or an antagonistic effect to vitamin D3.
It is an object of the present invention to provide new vitamin D3 derivatives having suppressing effect on neutrophilic infiltration and effective as treating agents for inflammatory respiratory diseases.
Another object of the present invention is to provide new vitamin D3 derivatives having antagonistic effect to vitamin D3 and effective as a treating agent for diseases.attributable to the overactivity of vitamin D3.
Still another object of the present invention is to provide methods for treating inflammatory respiratory diseases using these vitamin D3 derivatives as active ingredients.
Yet another object of the present invention is to provide methods for treating diseases attributable to the overactivity of vitamin D3 using these vitamin D3 derivatives as active ingredients.
A further object of the present invention is to provide pharmaceutical compositions containing these vitamin D3 derivatives as active ingredients.
According to the present invention, the above objects of the present invention are achieved by vitamin D3 derivatives expressed by the following general formula [1] or pharmaceutically permissible solvates thereof, 
{wherein, R01 and R02 are each independently a hydrogen atom, a trimethylsilyl group, a triethylsilyl group, a t-butyldimethylsilyl group, an acetyl group, a methoxymethyl group or a tetrahydro-4H-pyran-2-yl group;
Z is one out of the following formulae (1-1), (1-2), (1-3), (1-4) or (1-5), 
xe2x80x83[in the above formulae (1-1) to (1-5),
m is an integer of 0 to 2;
n is an integer of 0 to 2;
Xxe2x80x2 is an oxygen atom or NH;
R11 and R12 are identical to or different from each other, and express a hydrogen atom or a C1-C4 alkyl group;
K, L and M take each a hydrogen atom; M is a hydrogen atom, and K and L together express a single bond and express a double bond in cooperation with the single bond already shown in the formula; or K is a hydrogen atom, and L and M together express a single bond and express a double bond in cooperation with the single bond already shown in the formula;
R21, R22 and R23 are identical to or different from each other, and they are a hydrogen atom, a hydroxy group, a carboxyl group, a trifluoromethyl group, a pentafluoroethyl group, a C1-C4 alkyloxycarbonyl group, a C2-C5 acyloxy group, a C1-C4 alkyloxy group or a C1-C4 alkyl group which may be substituted with a hydroxyl group, a C2-C5 acyloxy group or a C1-C4 alkyloxy group, or R21 and R22 together may express a C3-C6 cyclic alkyl group in cooperation with the carbon atom to which they are bonded;
Q expresses  greater than C(xe2x80x94F)xe2x80x94R31 or  greater than Nxe2x80x94R31, and herein R31 is a hydrogen atom, a hydroxyl group, a trifluoromethyl group, a pentafluoroethyl group, a C2-C5 acyloxy group, a C1-C4 alkyloxy group or a C1-C4 alkyl group which may be substituted with a hydroxy group, a C2-C5 acyloxy group or a C1-C4 alkyloxy group;
R32, R33, R34 and R35 are identical to or different from each other, and they are a hydrogen atom, a hydroxyl group, a C1-C4 alkyl group or a C2-C5 acyloxy group;
A and B are identical to or different from each other, and they express a hydrogen atom or a hydroxyl group, or together express a single bond and form a double bond in cooperation with the single bond already shown in the formula;
X and Y together express a carbonyl group in cooperation with the carbon atom to which they are bonded, one of them is a hydrogen atom and the other is a hydroxyl group, or one of them is a hydrogen atom and the other is a C2-C5 acyloxy group;
R41 and R42 are identical to or different from each other, and they express a hydrogen atom, a hydroxyl group, a trifluoromethyl group, a pentafluoroethyl group, a C2-C5 acyloxy group, a C1-C4 alkyloxy group or a C1-C4 alkyl group which may be substituted with a hydroxyl group, a C2-C5 acyloxy group or a C1-C4 alkyloxy group, or both the members together express a C1-C5 alkylidene group, or they express a C3-C6 cyclic alkyl group in cooperation with the carbon atom to which they are bonded;
R43 and R44 are identical to or different from each other, and they express a hydrogen atom, a hydroxyl group, a trifluoromethyl group, a pentafluoroethyl group, a C2-C5 acyloxy group, a C1-C4 alkyloxy group or a C1-C4 alkyl group which may be substituted with a hydroxyl group, a C2-C5 acyloxy group or a C1-C4 alkyloxy group, or both the members together express a C1-C5 alkylidene group, or express a C3-C6 cyclic alkyl group in cooperation with the carbon atom to which they are bonded;
R45 and R46 are identical to or different from each other, and they express a hydrogen atom, a hydroxyl group, a trifluoromethyl group, a pentafluoroethyl group, a C2-C5 acyloxy group, a C1-C4 alkyloxy group or a C1-C4 alkyl group which may be substituted with a hydroxyl group, a C2-C5 acyloxy group or a C1-C4 alkyloxy group;
D and E express each a hydrogen atom, D is a hydroxy group and E expresses a hydrogen atom, D and E together express a single bond and express a double bond in cooperation with the single bond already shown in the formula, or E and R41 together express a single bond and express a double bond in cooperation with the single bond already shown in the formula, wherein D expresses a hydrogen atom or a hydroxy group; and R42 expresses a hydrogen atom, a hydroxyl group, a trifluoromethyl group, a pentafluoroethyl group, a C2-C5 acyloxy group, a C1-C4 alkyloxy group or a C1-C4 alkyl group which may be substituted with a hydroxyl group, a C2-C5 acyloxy group or a C1-C4 alkyloxy group;
R51 expresses xe2x80x94CONR511R512, xe2x80x94COR513 or xe2x80x94C(OH) R514R515R515, wherein R511 and R512 are identical to or different from each other, and they are a hydrogen atom or a C1-C4 alkyl group, or both the members together express a nitrogen-containing C3-C8 alkyl ring or a morpholino group in cooperation with the nitrogen atom to which they are bonded; and R513, R514 and R515 are identical to or different from each other, and they express a C1-C4 alkyl group;
R52 expresses a methyl group, an ethyl group, a trifluoromethyl group or a pentafluoroethyl group,
with the proviso that the following compounds (a), (b) and (c) are excluded,
(a) a compound in which the groups of one combination out of R21 and R22, R32 and R33, R34 and R35, R41 and R42, R43 and R44, and R45 and R46 are both hydroxy groups, both alkyloxy groups, or a hydroxy group and an alkyloxy group,
(b) a compound expressed by the above formula (1) in which Z is the following formula (1-6), 
xe2x80x83(wherein, p and q are each 0 or the integer 1; R6 is a hydrogen atom or a C1-C4 alkyl group), and
(c) a compound of the following formula (2), 
xe2x80x83(wherein, R01 and R02 are defined in the same manner as in the above formula (1); the configuration of the carbon atom at the 20-position is (R)-configuration; R7 is a methyl group or a methylene group; when R7 is a methylene group, the bond between R7 and the carbon atom at the 26-position is double bond)}.
When the structure of a compound of the above formula (1) has an asymmetric carbon, the configuration of the asymmetric carbon may be either (S)-configuiation or (R)-configuration as far as it is not especially specified, further, when L and M, A and B, D and E, or E and R41 together form a double bond, the configuration of the double bond may be either (E)-configuration or (Z)-configuration, and furthermore, the present invention includes mixtures of these various isomers at an arbitrary ratio.
In addition, according to the present invention, above objects of the present invention. are achieved by therapeutic methods for inflammatory respiratory diseases using above vitamin D3 derivatives or pharmaceutically permissible solvates thereof in therapeutically effective amounts as active ingredients.
Further, according to the present invention, above objects of the present invention are achieved by therapeutic methods for diseases attributable to the overactivity of vitamin D3 using the above vitamin D3 derivatives or pharmaceutically permissible solvates thereof in therapeutically effective amounts as active ingredients.
Further, according to the present invention, the above objects of the present invention are achieved by pharmaceutical compositions consisting of the above vitamin D3 derivatives or pharmaceutically permissible solvates thereof, and pharmaceutically permissible supports.
Furthermore, the above objects of the present invention are achieved by treating agents for inflammatory respiratory diseases containing vitamin D3 derivatives expressed by the following general formula (3) or pharmaceutically permissible solvates thereof in therapeutically effective amounts as activemingredients, 
(wherein, R01, R02 and R7 are defined in the same manner as in the above formula (2)).
Terms used in the present invention are defined as follows.
The term xe2x80x9cC2-C5 acyloxy groupxe2x80x9d expresses a normal, branched or cyclic aliphatic hydrocarbon carbonyloxy group having a carbon number of 2 to 5. Concrete examples of the group include acetoxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy, isovaleryloxy, pivaloyloxy, cyclopropylcarbonyloxy, cyclopropylacetoxy and cyclobutylcarbonyloxy groups, etc.
The term xe2x80x9cC1-C4 alkyloxy groupxe2x80x9d expresses a normal, branched or cyclic aliphatic hydrocarbon oxy group having a carbon number of 1 to 4. Concrete examples of the group include methoxy, ethoxy, propoxy, butoxy, isopropoxy, isobutoxy, s-butoxy, t-butoxy and cyclopropylmethyloxy groups, etc.
The term xe2x80x9cC1-C4 alkyloxycarbonyl groupxe2x80x9d expresses a normal, branched or cyclic aliphatic hydrocarbon oxycarbonyl group having a carbon number of 1 to 4. Concrete examples of the group include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, isopropoxycarbonyl, isobutoxycarbonyl, s-butoxycarbonyl, t-butoxycarbonyl and cyclopropylmethyloxycarbonyl groups, etc.
The term xe2x80x9cC3-C6 cyclic alkyl groupxe2x80x9d expresses a cyclic aliphatic hydrocarbon group having a carbon number of 3 to 6. Concrete examples of the group include cyclopropyl, methylcyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups, etc.
The term xe2x80x9cnitrogen-containing C3-C8 alkyl ringxe2x80x9d expresses an aliphatic hydrocarbon ring which has a carbon number of 3 to 8 and contains a nitrogen atom in a ring. Concrete examples of the ring include aziridine, azetidine, pyrrolidine, imidazolidine, pyrazolidine, piperidine and piperazine rings, etc.
The term xe2x80x9cC1-C4 alkyl group which may be substituted with a hydroxy group, a C2-C5 acyloxy group or a C1-C4 alkyloxy group xe2x80x9d expresses a normal, branched or cyclic aliphatic hydrocarbon group having a carbon number of 1 to 4 whose arbitrary position may be substituted with a hydroxy group, an acyloxy group having a carbon number of 2 to 5 or an alkyloxy group having a carbon number of 1 to 4. Examples of the group include methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, s-butyl, t-butyl, cyclopropylmethyl, cyclobutyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, acetoxymethyl, propionyloxymethyl, butyryloxymethyl, acetoxyethyl, propionyloxyethyl, butyryloxyethyl, acetoxypropyl, propionyloxypropyl, butyryloxypropyl, methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, methoxypropyl and ethoxypropyl groups, etc.
In the above formula (1), R01 and R02 are each independently a hydrogen atom, a trimethylsilyl group, a triethylsilyl group, a t-butyldimethylsilyl group, an acetyl group, a methoxymethyl group or tetrahydro-4H-pyran-2-yl. Among these groups, the case where both of R01 and R02 are hydrogen atoms, trimethylsilyl groups, triethylsilyl groups or t-butyldimethylsilyl groups is preferable, and further the case where they are hydrogen atoms is the most preferable.
In the above formula (1), Z expresses one of the above-mentioned formulae (1-1), (1-2), (1-3), (1-4) and (1-5).
In the above formula (1), m is an integer of 0 to 2, and 0 or 1 is especially preferable.
In the above formula (1), n is an integer of 0 to 2, and 0 or 1 is especially preferable.
In the abo ve formula (1), Xxe2x80x2 is an oxygen atom or NH, and an oxygen atom is especially preferable.
In the above formula (1), R11 and R12 are identical to or different from each other, and they express a hydrogen atom or a C1-C4 alkyl group. A hydrogen atom, a methyl group or an ethyl group is especially preferable.
In the above formula (1), K, L and M are all hydrogen atoms; M is a hydrogen atom, and K and L together express a single bond and express a double bond in cooperation with the single bond already shown in the formula; or K is a hydrogen atom, and L and M together express a single bond and express a double bond in cooperation with the single bond already shown in the formula. The cases where M is a hydrogen atom, and K and L together express a single bond and express a double bond in cooperation with the single bond already shown in the formula; and K is a hydrogen atom, and L and M together express a single bond and express a double bond in cooperation with the single bond already shown in the formula are especially preferable. Further, the case where K is a hydrogen atom, and L and M together express a single bond and express a double bond in cooperation with the single bond already shown in the formula is the most preferable.
In the above formula (1), R21, R22 and R23 are identical to or different from each other, and they are a hydrogen atom, a hydroxy group, a carboxyl group, a trifluoromethyl group, a pentafluoroethyl group, a C1-C4 alkyloxycarbonyl group, a C2-C5 acyloxy group, a C1-C4 alkyloxy group, a C1-C4 alkyl group which may be substituted with a hydroxyl group, a C2-C5 acyloxy group or a C1-C4 alkyloxy group; or R21 and R22 together may express a C3-C6 cyclic alkyl group in cooperation with the carbon atom to which they are bonded. Among them, the case where R21 and R22 are identical to or different from each other, and they are a hydrogen atom, a hydroxyl group or a C1-C4 alkyl group, or R21 and R22 together express a C3-C6 cyclic alkyl group in cooperation with the carbon atom to which they are bonded is preferable. Further, the case where R21 and R22 are a hydrogen atom, a hydroxyl group, a methyl group, an ethyl group or an n-propyl group, or both the members together form a cyclopropyl group in cooperation with the carbon atom to which they are bonded is especially preferable. In addition, R23 is preferably a hydrogen atom or a hydroxyl group.
Preferable examples of the combination of R21, R22 and R23 include (a) R21, R22 and R23 are all hydrogen atoms, (b) R21 and R22 are methyl groups, and R23 is a hydrogen atom, (c) the combination of R21 and R22 is the case where they are a methyl group and a hydroxyl group, and R23 is a hydrogen atom, (d) the combination of R21 and R22 is the case where they are a methyl group and a hydroxyl group, and R23 is a hydroxyl group and (e) R21 and R22 together form a cyclopropyl group in cooperation with the carbon atom to which they are bonded, and R23 is a hydrogen atom.
In the above formula (1), Q expresses  greater than C(xe2x80x94F)xe2x80x94R31 or  greater than Nxe2x80x94R31, and herein R31 is a hydrogen atom, a hydroxyl group, a trifluoromethyl group, a pentafluoroethyl group, a C2-C5 acyloxy group, a C1-C4 alkyloxy group, or a C1-C4 alkyl group which may be substituted with a hydroxy group, a C2-C5 acyloxy group or a C1-C4 alkyloxy group. Among them, R31 is especially preferably a hydrogen atom, a hydroxyl group or, a C1-C4 alkyl group which may be substituted with a hydroxy group, a C2-C5 acyloxy group or a C1-C4 alkyloxy group. Further, R31 is the most preferably a hydrogen atom, a hydroxyl group or a methyl group.
In the above formula (1), R32, R33, R34 and R35 are identical to or different from each other, and they are a hydrogen atom, a hydroxyl group, a C1-C4 alkyl group or a C2-C5 acyloxy group. Among them, a hydrogen atom or a C1-C4 alkyl is preferable, and further a hydrogen atom is the most preferable.
In the above formula (1), A and B are identical to or different from each other, and they express a hydrogen atom or a hydroxyl group, or both the members together express a single bond and form a double bond in cooperation with the single bond already shown in the formula. Among them, the case where A and B are both hydrogen atoms, A is a hydroxyl group and B is a hydrogen atom, or they together express a single bond and form a double bona in cooperation with the single bond already shown in the formula is preferable.
In the above formula (1), X and Y together express a carbonyl group in cooperation with the carbon atom to which they are bonded, one of them is a hydrogen atom and the other is a hydroxyl group, or one of them is a hydrogen atom and the other is a C2-C5 acyloxy group. Especially the case where X and Y together express a carbonyl group in cooperation with the carbon atom to which they are bonded is preferable.
In the above formula (1), R41 and R42 are identical to or different from each other, and they express a hydrogen atom, a hydroxyl group, a trifluoromethyl group, a pentafluoroethyl group, a C2-C5 acyloxy group, a C1-C4 alkyloxy group or a C1-C4 alkyl group which may be substituted with a hydroxyl group, a C2-C5 acyloxy group or a C1-C4 alkyloxy group. In addition, both the members together express a C1-5 alkylidene group, or they together express a C3-C6 cyclic alkyl group in cooperation with the carbon atom to which they are bonded. Especially, the case where they express hydrogen atoms, or both the members together express a methylene group is preferable.
In the above formula (1), R43 and R44 are identical to or different from each other, and they express a hydrogen atom, a hydroxyl group, a trifluoromethyl group, a pentafluoroethyl group, a C2-C5 acyloxy group, a C1-C4 alkyloxy group, or a C1-C4 alkyl group which may be substituted with a hydroxyl group, a C2-C5 acyloxy group or a C1-C4 alkyloxy group. In addition, both the members together express a C1-C5 alkylidene group, or they together express a C3-C6 cyclic alkyl group in cooperation with the carbon atom to which they are bonded. Especially, the case where they express hydrogen atoms, or both the members together express a methylene group is preferable.
In the above formula (1), R45 and R46 are identical to or different from each other, and they express a hydrogen atom, a hydroxyl group, a trifluoromethyl group, a pentafluoroethyl group, a C2-C5 acyloxy group, a C1-C4 alkyloxy group or a C1-C4 alkyl group which may be substituted with a hydroxyl group, a C2-C5 acyloxy group or a C1-C4 alkyloxy group. Especially, the case where they are a hydrogen atom, a hydroxyl group, a methyl group or an ethyl group, and further the case where they are hydrogen atoms is the most preferable.
In the above formula (1), D and E both express hydrogen atoms, D is a hydroxy group and E expresses a hydrogen atom, or D and E together express a single bond and express a double bond in cooperation with the single bond already shown in the formula. In addition, E and R41 together express a single bond and express a double bond in cooperation with the single bond already shown in the formula, wherein D expresses a hydrogen atom or a hydroxy group, and R42 expresses a hydrogen atom, a hydroxyl group, a trifluoromethyl group, a pentafluoroethyl group, a C2-C5 acyloxy group, a C1-C4 aLkyloxy group or a C1-C4 alkyl group which may be substituted with a hydroxyl group, a C2-C5 acyloxy group or a C1-C4 alkyloxy group. Especially, the case where D and E both are hydrogen atoms, D and E together express a single bond and express a double bond in cooperation with the single bond already shown in the formula, or D is a hydrogen atom, and E and R41 together express a single bond and express a double bond in cooperation with the single bond already shown in the formula is preferable.
In the above formula (1), R51 expresses xe2x80x94CONR511R512, xe2x80x94COR513 or xe2x80x94C(OH) R514R515. Herein, R511 and R512 are identical to or different from each other, and they are a hydrogen atom or a C1-C4 alkyl, or both the members together express a nitrogen-containing C3-C8 alkyl ring or a morpholino group in cooperation with the nitrogen atom to which they are bonded; and R513, R514 and R515 are identical to or different from each other, and they express a C1-C4 alkyl group. Especially, R5i is preferably xe2x80x94CONR511R512 or xe2x80x94COR513. In addition, R511 and R512 are preferably a methyl group or an ethyl group, or both the members together express an aziridine, pyrrolidine, piperidine or morpholino ring in cooperation with the nitrogen atom to which they are bonded. R513, R514 and R515 are preferably a methyl group or an ethyl group.
In the above formula (1), R52 expresses a methyl group, an ethyl group, a trifluoromethyl group or a pentafluoroethyl group. Especially, a methyl group is preferable.
Vitamin D3 derivatives of the present invention can be optionally converted into pharmaceutically permissible solvates thereof. Examples of such a solvent include water, methanol, ethanol, propyl alcohol, isopropyl alcohol, butanol, t-butanol, acetonitrile, acetone, methyl ethyl ketone, chloroform, ethyl acetate, diethyl ether, t-butyl methyl ether, benzene, toluene, DMF, DMSO, etc. Especially, water, methanol, ethanol, propyl alcohol, isopropyl alcohol, acetonitrile, acetone, methyl ethyl ketone and ethyl acetate may be cited as preferable examples.
Preferable concrete examples of the vitamin D3 derivative of the present invention expressed by the above formula (1) are shown in Tables 1-1-1, 1-2-1, 1-3-1, 1-3-2, 1-4-1, 1-4-2 and 1-5-1. Further, in these compounds, when an asymmetric carbon is included in the structure of a compound, the configuration of the asymmetric carbon can be either (S)-configuration or (R)-configuration as far as it is not especially specified. When L and M, A and B, D and E, or E and R41 together form a double bond, the configuration of the double bond includes both (E)-configuration and (Z)-configuration. In addition, for the convenience of reading, a subscript is written in a normal size in a table, for example, xe2x80x9cCH2xe2x80x9d is written as xe2x80x9cCH2xe2x80x9d.
In addition, preferable concrete examples of the compound expressed by the above formula (3) used in the present invention include compounds whose R01 and R02 are hydrogen atoms, and R7 is a methylene group, and compounds whose R01 and R02 are hydrogen atoms, and R7 is a methyl group. Further, when a compound of the examples has an asymmetric carbon in its structure, the configuration of the carbon includes both (S)-configuration and (R)-configuration as far a""s it is not especially specified.
A vitamin D3 derivative expressed by the above formula (1) can be produced by subjecting a compound expressed by the following formula (4) and an ene-yne compound expressed by the following formula (5) to a coupling reaction in the presence of a palladium catalyst, for example, as shown by Trost, et al. (J. Am. Chem. Soc., 114, 9836-9845 (1992)) (Scheme 1). 
(in the above formulae (4) and (5), Z, R01 and R02 are defined in the same manner as in the above formula (1), and Y is an iodine atom or a bromine atom).
As the palladium catalyst in the coupling reaction, for example, a mixture of a 0- or 2-valent organic palladium compound and a trisubstituted phosphorus compound [molar ratio is (1:1) to (1:10)] is used. Examples of the palladium compound may include tetrakis(triphenylphosphine)palladium, tris(dibenzylideneacetone)palladium, tris(dibenzylideneacetone)palladium chloroform and palladium acetate. Further, examples of the trisubstituted phosphorus compound include triphenylphosphine, tributylphosphine, etc. As the palladium catalyst of the combination of both the components, the combinations of tris(dibenzylideneacetone)palladium and triphenylphosphine, and tris(dibenzylideneacetone)palladium chloroform and triphenylphosphine [molar ratio of (1:1) to (1:10)] are preferable. Further, an organic palladium compound is used in the range of 1 to 100 mol %, preferably 5 to 30 mol % based on a compound expressed by the above formula (4). In order to produce an active palladium, a trisubstituted phosphorus compound is used in an amount of 1 to 10 equivalents to an organic palladium compound.
Herein, a compound expressed by the above formula (4) and an ene-yne compound expressed by the above formula (5) perform stoichiometrically equimolar reaction, but in order to surely complete the reaction, it is preferable that one component, which is commonly easier in availability, is used in a little excess than the other.
Examples of the organic solvent to be used in the coupling reaction include a hydrocarbon solvent such as hexane or toluene, an ether solvent such as tetrahydrofuran or dioxane, a water-soluble solvent such as N,N-dimethylformamide or acetonitrile, a mixed solvent of them, etc., and they are preferably used after sufficient deaeration. As the reaction temperature, a temperature ranging from room temperature to the boiling temperature of the solvent is commonly used. The reaction time depends on the reaction solvent and the reaction temperature used in the reaction, and it is commonly preferable that the reaction is continued until either the compound expressed by the above formula (4) or the ene-yne compound expressed by the above formula (5) disappears, when determined by using an analytical means such as thin layer chromatography. Further, it is preferable that the reaction is carried out, for example, in the presence of a base such as triethylamine or diisopropylamine for trapping hydrogen chloride, besides a. palladium catalyst. As for the amount of the base used for the reaction, one equivalent or more based on a compound expressed by the above formula (4) is preferable, and optionally, the base may be used as the solvent at the same time.
A compound expressed by the above formula (4) (Z=(1-1); n=0), (Z=(1-2); n=0), (Z=(1-3)) or (Z=(1-4)) which is used as a raw material in the above-mentioned Scheme 1 can be produced from an aldehyde compound expressed by the following formula (6), for example, as shown in the following Scheme 2. 
(in the above formula (6), m and Z are defined in the same manner as in the above formula (1), and Y is a bromine atom or an iodine atom).
The aldehyde compound (6) which is used in the reaction and in which the carbon atom marked with an asterisk * has (R)-configuration, and m is 0, 1 or 2 can be produced, for example, by combining known processes as shown the following in Schemes 3, 4 and 5. 
Further, a compound corresponding the compound expressed by the formula (6) and having an (S)-configuration regarding the carbon atom which is marked with an asterisk * can be produced, for example, by using an intermediate aldehyde obtained by Scheme 4 through a process shown by the following Scheme 6. 
A compound expressed by the above formula (4) (Z=(1-1); Xxe2x80x2=oxygen atom; n=0) can be produced, for example, through a process shown by the following Scheme 7 or 8 by using an aldehyde compound (6) obtained through the process shown above. 
Further, a compound expressed by the above formula (4) (Z=(1-1); Xxe2x80x2=NH; n=0) can be produced, for example, through a process shown by the following Scheme 9 or 10. 
Further, a compound expressed by the above formula (4) (Z=(1-2); Xxe2x80x2=oxygen atom; n=0) can be produced, for example, through a process shown by the following Scheme 11. 
Further, a compound expressed by the above formula (4) (Z=(1-2); Xxe2x80x2=NH; n=0) can be produced, for example, through a process shown by the following Scheme 12. 
A compound expressed by the above formula (4) (Z=(1-2); Xxe2x80x2=oxygen atom; n=0) in which especially R21 and R22 together form a cyclopropane ring in cooperation with the carbon atom to which they are bonded can be produced, for example, through a process shown by the following Scheme 13. 
Further, a compound expressed by the above formula (4) (Z=(1-3) or (1-4)) can be derived from a compound (6) by using reactions shown by the below-mentioned Schemes 28 to 33.
A compound expressed by the above formula (4) (Z=(1-1); n=1 or 2) or (Z=(1-2); n=1 or 2), which is used as a raw material in the above Scheme 1, can be produced, for example, by deriving a compound (8) from a compound (7) through the protection of the hydroxy group and oxidation, obtaining a compound (9) through the construction of a ring structure by a below-mentioned process, subsequently deprotecting the protected hydroxyl group, and oxidizing and halomethylating the hydroxy group as shown in the following Scheme 14. 
(in the above formulae (4), (7), (8) and (9), m and Z are defined in the same manner as in the above formula (1); Y is a bromine or iodine atom; n is an integer of 1 or 2; PG is a protecting group for a hydroxy group).
The compound (7) used in the Scheme 14 whose m is 1, 2 or 3 can be produced, for example, from an aldehyde compound (10) obtained from an intermediate of the above-mentioned Schemes 3 to 6 by combining known processes as shown in the following Scheme 15. 
A compound expressed by the above formula (9) (Z=(1-1); Xxe2x80x2=oxygen; n=1 or 2) can be produced, for example, by using a compound (8), which is obtained by the above-mentioned process, through the process shown by the following Scheme 16, 17 or 18. 
Further, a corupound expressed by the above formula (4) (Z=(1-1); Xxe2x80x2=NH; n=1 or 2) can be produced, for example, through the process shown by the following Scheme 19, 20 or 21. 
Further, a compound expressed by the above formula (4) (Z=(1-2); Xxe2x80x2=oxygen atom; n=1 or 2) can be produced, for example, through the process shown by the following Scheme 22 or 23. Yet, the dioxolanone compound (11), which is used in Scheme 22, can be obtained by a known method (for example, Seebach, et al., Tetrahedron, 40, 1313 (1984)). 
Further, a compound expressed by the above formula (4) (Z=(1-2); Xxe2x80x2=NH; n=1 or 2) can be produced, for example, through the process shown by the following Scheme; 24. 
A compound expressed by the above formula (4) (Z=(1-5)), which is used as a raw material in the above Scheme 1, can be produced, for example, from a compound (12) as shown in the following Scheme 25. 
Further, a compound corresponding the compound (12), which is used in the preceding process and whose asymmetric center marked by an asterisk * has (R)-configuration, can be produced, for example, through combining known processes as shown in the following Scheme 26. 
Further, implemental methods of these reactions are concretely described in International Patent Publication WO95/33716.
In addition, the compound (12) whose asymmetric center shown by an asterisk * has (S)-configuration can be produced, for example, by treating an intermediate (13) with a base in the Scheme 26 and subjecting the obtained epimer to a reaction in the same manner as in the Scheme 26.
Further, a vitamin D3 derivative expressed by the above formula (1) can be produced, for example, by converting the compound (15) obtainable through the photoisomerization of a compound expressed by the formula (14), or photoisomerizing the compound (16) derived from the compound (14), as shown in the following Scheme 27. Yet, the compound (16) can be derived from the compound (14) in the same manner as in the below-mentioned process in which the compound (1) is derived from the compound (15). 
(in the formulae (1), (14), (15) and (16) of Scheme 27, m, Z, R01 and R02 are defined in the same manner as in the above formula (1)).
The compound (15) can be converted to the compound (1) (Z=(1-3)), for example, by subjecting the compound (15) and the compound (17) to aldol reaction and optionally further combining dehydration, reduction, hydrogenation and others as shown in the following Scheme 28. 
Examples of the base catalyst in the above aldol reaction can include an inorganic base catalyst such as potassium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide or sodium hydride, an organic base catalyst such as 1,8-diazabicyclo[5.4.0]undecene (DBU), and an organo metallic base catalyst such as lithium diisopropylamide, lithium hexamethyldisilylamide or sodium hexamethyldisilylamide. Among them, sodium hydroxide, potassium hydroxide, lithium diisopropylamide or lithium hexamethyldisilylamide can be cited as a preferable example. The amount of the base catalyst to be used is 0.1-10 equivalents, preferably 0.5-3 equivalents based on the aldehyde to be used as a raw material. Further, an additive for stimulating the reaction may be added to the reaction system as required. Here, an aldehyde expressed by the above formula (15) carries out stoichiometrically equimolar reaction with a compound expressed by the above formula (17), but it is preferable that one component, which is easier in availability is used in a little excess than the other for certainly completing the reaction. Examples of the organic solvent to be used in the aldol reaction include an alcoholic solvent such as methanol or ethanol, a halogen containing solvent such as methylene chloride, chloroform or carbon tetrachloride, a hydrocarbon solvent such as hexane or toluene, an ether solvent such as tetrahydxofuran or dioxane, a water-soluble solvent such as N,N-dimethylformamide or acetonitrile, a mixed solvent of them, etc. The solvent can be selected considering the solubilities and the reactivities of the compounds. As for reaction temperature, a temperature in the range from xe2x88x9278xc2x0 C. to the boiling point of the solvent is generally used. A reaction time depends on the base catalyst, the reaction solvent and the reaction temperature used. It is commonly preferable that the reaction is continued until either the compound expressed by the above formula (17) or the aldehyde expressed by the above formula (15) disappears when determined by using an analytical means such as thin layer chromatography.
Examples of the dehydrating agent to be used in the dehydration 30 reaction include an acid such as potassium hydrogensulfate, oxalic acid, p-toluenesulfonic acid, iodine or anhydrous copper sulfate, a halogenating agent such as thionyl chloride or phosphoric acid chloride, a sulfonating agent such as methanesulfonyl chloride, etc. The agent is used in an amount of 1-10 equivalents, preferably 1-5 equivalents based on the raw material.
In the reductive reaction, sodium borohydride cesium chloride , diisobutylaluminum hydride (DIBAH), 9-borabicyclo[33.1]nonane (9-BBN), lithium n -butylborohydride, K-Selectride(copyright), tri-isobutylaluminium, etc., may be used.
In the hydrogenation, sodium borohydride, Na2S2O4, NaHTe, tri-n-butyltin hyedride, K-Selectride(copyright) or sodium aluminum hydride-cuprous chlride, or Birch reduction, etc., is applicable.
Further, the compound (15) can be converted to the compound (1) (Z=(1-3); Q is  greater than C(xe2x80x94F)xe2x80x94R31) by carrying out aldol reaction between the compound (15) and a compound (18), and subsequently subjecting the obtained ketone to silylation-enolation followed by fluorization as shown in the following Scheme 29. 
Examples of a fluorinating agent used in the fluorination include N-fluoropyridinium, triflate, N-fluoropyridinium trifluoromethanesulfonate, N-fluoro-2,4,6-trimethylpyridinium triflate, N-fluoro-3,5-dichloropyridinium triflate, N-fluoro-2,6-dichloropyridinium triflate, N-fluoro-4,6-dimethylpyridinium-2-sulfonate, N-fluoro-4-methylpyridinium-2-sulfonate, N-fluoro-6-(trifluoromethyl)pyridinium-2-sulfonate, N-fluoro-4,6-bis(trifluoromethyl)pyridinium-2-sulfonate, CsSO4F, XeF2, CF3OF, CH3CO2F, etc.
The compound (15) can be converted to the compound (1) (Z=(1-4); R41=Dxe2x95x90Exe2x95x90hydrogen atom), for example, by subjecting the compound (15) to reduction, halogenation, halogen-metal exchange reaction, metal-metal exchange reaction and 1,4-addition as shown in the following Scheme 30. 
The above reduction can be carried out, for example, by reducing the compound with a hydride reagent such as sodium borohydride or lithium aluminumhydride.
The halogenation can be carried out, for example, with the combination of carbon tetrabromide or carbon tetrachloride, and triphenylphosphine.
Examples of the metal reagent used in the above-mentioned metal-halogen exchange reaction include butyllithium, magnesium metal, samarium diiodide, etc., and it is used in an amount of 1-5 equivalents based on the raw material.
The metal-metal exchange reaction is optionally carried out successively after the metal-halide exchange reaction, and the metal-metal exchange reaction is performed, for example, by using copper iodide, copper bromide, an adequate complex of the copper halide, copper cyanide or the like.
In the 1,4-addition, an additive can be used, and the additive is, for example, a silylating agent such as trimethylsilyl triflate or chlorotrimethylsilane, a ligating compound such as hexamethylphosphoric triamide (HMPA) or triphenylphosphine, or a combination of these compounds. Especially, the combination of chlorotrimethylsilane and HMPA is cited as a preferable additive.
The metal-halogen exchange reaction, metal-metal exchange reaction and 1,4-addition in the above Scheme 30 are preferably carried out successively in a single reaction system without performing after-treatments.
Out of the compounds (1) (Z=(1-4)) obtained in the above Scheme 30, a compound in which R42 is a hydrogen atom and/or R43 and R44 are both hydrogen atoms can be converted to a compound (1) (Z=(1-4)) having a methylene group at the xcex1-position to the carbonyl group by further methylenating it in one step or two steps as shown in the following Scheme 31. 
In order to carry out the methylenation in one step, for example, N-methylanilinium trifluoroacetate and paraformaldehyde can be used.
Yet, the two step methylenation can be carried out by adding an iminium salt followed by deamination. In this reaction, examples of the base include potassium tert-butoxide, sodium hydride, potassium hydride, sodium ethoxide, lithium diisopropylamide, lithium hexamethyldisilylamide, etc., and examples of the iminium salt include N,N-dimethyl(methylene)ammonium iodide, N,N-dimethyl(methylene)ammonium trifluoroacetic acid, etc. Further, the iminium salt may be generated in the reaction system from a secondary amine, and formaldehyde or its equivalent.
The deamination is carried out by heat treatment, conversion to an ammonium salt or the like.
Further, the compound (15) can be converted to a compound (1) (Z=(1-4); R41xe2x95x90Dxe2x95x90E=hydrogen atom) or (Z=(1-4); D=hydrogen atom, and E and R41 together express a single bond and express a double bond in cooperation with the single bond already shown in the formula), for example, via the enol ether (19) which is obtained by coupling the compound (15) with an unsaturated enone as shown in the following Scheme 32. 
The coupling reaction and the conversion of the compound (19) to the compound (1) in the above Scheme 32 can be carried out by known processes.
Further, the compound (15) can be converted to the compound (1) (Z=(1-4); both D and E are hydrogen atoms, D is a hydroxyl group and E is a hydrogen atom, or D and E together express a single bond and express a double bond in cooperation with the single bond already shown in the formula; the combination of R41 and R42 is (a hydrogen atom and a hydroxyl group), (a hydrogen atom and a C2-C5 acyloxy group), (a C1-C4 alkyl group which may be substituted with a hydroxyl group, a C2-C5 acyloxy group or a C1-C4 alkyloxy group, and a hydroxy group) or (a C1-C4 alkyl group which may be substituted with a hydroxyl group, a C2-C5 acyloxy group or a C1-C4 alkyloxy group, and a C2-C5 acyloxy group)), for example, by carrying out aldol reaction between the aldehyde (15) and a cycloalkanone (20) whose carbonyl group at the xcex1-position to the ketone is protected by acetal, and subsequently optionally carrying out dehydration, reduction or reaction with an organometallic reagent, acetal deprotection, and the like as shown in the following Scheme 33. 
The above-mentioned aldol reaction, dehydration and reduction can be carried out under the conditions of the above Scheme 28.
Examples of the organometallic reagent used in the reaction with an organometallic reagent include an organolithium compound, a Grignard reagent, an organocerium reagent and the like.
The removal of the acetal group in deprotection can be carried out by using toluenesulfonic acid, trifluoroacetic acid, sulfuric acid, toluenesulfonic acid-pyridine complex or the like as a catalyst.
The conversion of the compound (15) to the compound (1) (Z=(114 1), (1-2) or (1-5)) also can be achieved by using reactions shown in the above Schemes 2 to 26.
The aldehyde expressed by the above formula (14) can be produced, for example, in a manner shown the following Schemes 34 and 35. That is, the compound (14) in which m is 0, 1 or 2 can be produce by using the compound (21) obtainable from vitamin D2 through a known process (International Patent Publication WO90/09991; Tetrahedron, 20, 4609-4619 (1987)) as a raw material. 
The compound of the above formula (1) which is obtained through a process shown above can be converted to a vitamin D3 derivative of the above formula (1) whose R01 and R02 are hydrogen atoms, by carrying out deprotection reaction as required.
The deprotection reaction can be carried out as shown below. When R01 and R02 are acetyl groups, common alkali hydrolysis, or a treatment with potassium cyanide, ammonium-methanol or the like can be used. When R01 and R02 are methoxymethyl groups or tetrahydro-4H-pyran-2-yl groups, the reaction can be carried out under acidic conditions, for example, by using hydrochloric acid, acetic acid, trifluoroacetic acid or the like, or pyridinium, p-toluenesulfonate (PPTS), LiBF4 or the like. When R01 and R02 are trimethylsilyl groups, triethylsilyl groups or t-butyldimethylsilyl groups, the reaction can be carried out according to a known method (for example, Caverly, Tetrahedron, 20, 4609-4619 (1987)), and as the deprotecting agent, for example, tetrabutylammonium fluoride, pyridinium p-toluenesulfonate, hydrogen fluoride, etc., may be used. Examples of the organic solvent to be used in the reaction include a halogen-containing solvent such as methylene chloride, chloroform or carbon tetrachloride, a hydrocarbon solvent such as hexane or toluene, an ether solvent such as tetrahydrofuran or dioxane, a water-soluble solvent such as N,N-dimethylformamide or acetonitrile, a mixed solvent of them, etc. The solvent may be selected in consideration of the solubility and the reactivity of the compound. The reaction temperature generally ranges from xe2x88x9220xc2x0 C. to the boiling point of the solvent. The reaction time depends on the dehydrating agent, deprotecting agent, reaction solvent and reaction temperature used, and it is commonly preferable that the reaction is continued until the starting material disappears when determined by using an analytical means such as thin layer chromatography.
Further, the above deprotection reaction may be carried out by using a reagent consisting of a combination of an alkali metal salt of tetrafluoroboric acid and a mineral acid, especially in the case where R01 and R02 are trimethylsilyl groups, triethylsilyl groups or t-butyldimethylsilyl groups. As the alkali metal salt of tetrafluoroboric acid, lithium tetrafluoroborate, sodium tetrafluoroborate or potassium tetrafluoroborate may be used, and as the mineral acid, hydrochloric acid, sulfuric acid, etc., may be used. It is preferable that the alkali metal salt of tetrafluoroboric acid is used in an amount of 1-3 equivalents based on the hydroxyl group to be deprotected, and the mineral acid is used in an amount of 0.05-3 equivalents. To the reaction solvent, reaction temperature and reaction time, the same conditions as in the above deprotection reaction may be applied. Especially, acetonitrile and methylene chloride are preferable as the solvent, the reaction temperature is preferably from 0xc2x0 C. to room temperature, and the reaction time is preferably from 10 min to about 1 hr.
Further, vitamin D3 derivatives expressed by the above formula (3) can be produced through a known process, for example, the process described in International Patent Publication WO95/33716.
Thus obtained vitamin D3 derivatives can be optionally converted into pharmaceutically permissible solvates shown above.
Furthermore, the present invention provides treating agents for inflammatory respiratory diseases containing vitamin D3 derivatives expressed by the above formula (1) or (3), or pharmaceutically permissible solvates thereof in therapeutically effective amounts and also methods for treating the diseases using the agents.
Preferable examples of the inflammatory respiratory diseases to be objective of the treating agents or the treating methods of the present invention include one or not less than two kinds of inflammatory respiratory diseases selected from a group consisting of acute upper airway infection, chronic sinusitis, allergic rhinitis, chronic lower airway infection, pulmonary emphysema, pneumonia, bronchial asthma, tuberculosis sequela, acute airway distress syndrome, cystic fibrosis and pulmonary fibrosis.
As an inflammatory respiratory disease which is objective of the present invention, we can select especially one or not less than two kinds of acute upper airway infections from a group consisting of, for example, common cold, acute pharyngitis, acute rhinitis, acute sinusitis, acute tonsillitis, acute pharyngitis, acute epiglottitis and acute bronchitis, or one or not less than two kinds of chronic lower airway infections from a group consisting of, for example, chronic bronchitis, diffuse panbronchiolitis and bronchiectasis.
Further, the present invention provides agents containing a vitamin D3 derivative expressed by the above formula (1) or a pharmaceutically. permissible solvate, thereof in a pharmaceutically effective amount for treating diseases selected from a group consisting of malignant tumors, rheumatoid arthritis, osteoporosis, diabetes mellitus, hypertension, alopecia, acne, psoriasis and dermatitis and methods for treating a group of the diseases using the treating reagents.
Furthermore, the present invention provides agents containing a vitamin D3 derivative expressed by the above formula (1) which is a compound having an antagonistic effect to vitamin D3 in a pharmaceutically effective amount for treating diseases selected from a group consisting of hypercalcemia attributable to excess vitamin D3, hypoparathyroidism and metabolic disorder of cartilage, and methods for treating a group of the diseases using the treating reagents. The hypercalcemia attributable to excess vitamin D3 means, for example, a disease such as sarcoidosis caused by the overproduction of vitamin D3 in tumorigenic macrophage-like cells or lymphocyte cells of a malignant lymphoma patient, or vitamin D3 toxipathy caused by the megadose of vitamin D3. The hypoparathyroidism is, for example, idiopathic or postoperative hypoparathyroidism caused by the depression of PTH production, or the like. The metabolic disorder of cartilage is, for example, a disease in which cartilage components are decomposed and decreased due to the lowering of the biosynthesis ability or the damage of collagen, proteoglucan, etc., in cartilage cells or substrates. Examples of the disease may include osteoarthritis, rheumatoid arthritis, rheumatic fever, etc.
Treating agents for various diseases of the present invention can be administered orally, or parentally through intravenous, subcutaneous, intramuscular, percutaneous, intranasal or intrarectal route or the like, or by inhalation.
Dosage forms for oral administration include tablets, pills, powders, granules, liquids, suspensions, syrups, capsules, etc.
The tablets are formulated according to a conventional process by using additives consisting of an excipient such as lactose, starch, calcium carbonate, crystalline cellulose or silicic acid; a binder such as carboxymethylcellulose, methylcellulose, calcium phosphate or polyvinylpyrrolidone; a disintegrator such as sodium alginate, sodium bicarbonate, sodium laurylsulfate or stearic acid monoglyceride; a humectant such as glycerin; an absorbent such as kaolin or colloidal silica; a lubricant such as talc or granular boric acid, etc.
The pills, powders and granules are prepared by conventional processes also using additives similar to those mentioned above.
Liquid preparations such as the liquids, suspensions and syrups can be formulated also according to conventional processes. As a carrier, for example, a glycerol ester such as tricaprylin, triacetin or an iodized poppy oil fatty acid ester; water; an alcohol such as ethanol; or an oily base such as liquid paraffin, coconut oil, soybean oil, sesame oil or corn oil is used.
The capsules are formulated by filling a powdery, granular or liquid pharmaceutical composition, or the like, in gelatin capsules, or the like.
Dosage forms for intravenous, subcutaneous and intramuscular administration include injections in the forms of sterilized aqueous solutions, non-aqueous solutions, etc. In an aqueous solution, for example, a physiological saline solution or the like is used as a solvent. In a non-aqueous solution, for example, propylene glycol, polyethylene glycol, a vegetable oil such as olive oil, an organic ester which is acceptable for injection such as ethyl oleate or an iodized poppy oil fatty acid ester, or the like is used as a solvent. To the pharmaceutical preparations for injection are optionally added an isotonizing agent, a preservative, a humectant agent, an emulsifier, a dispersant, a stabilizer, etc., and the preparation may be sterilized by applying an adequate treatment such as filtration through a bacterium-retaining filter, blending of a germicide or irradiation. Also, the preparation may be prepared as an aseptic solid preparation which is used by dissolving in sterilized water or a sterilized solvent for injection just prior to use.
Further, a compound of the present invention may be used in the form of a clathrate compound prepared by using xcex1, xcex2 or xcex3-cyclodextrin, a methylated cyclodextrin, or the like. The compound may be used also as an injection of lipoid form.
Dosage forms for percutaneous administration preparations include ointments, creams, lotions, solutions, etc.
Examples of the base of an ointment include a fatty acid such as castor oil, olive oil, sesame oil or safflower oil; lanolin; white, yellow or hydrophilic vaseline; wax; a higher alcohol such as oleyl alcohol, isostearyl alcohol, octyldodecanol or hexyldecanol; a glycol such as glycerin, diglycerin, ethylene glycol, propylene glycol, sorbitol or 1,3-butanediol; etc. Further, as a solubilizing agent for a compound of the present invention, ethanol, dimethyl sulfoxide polyethylene glycol, etc., may be compounded. Optionally, a preservative such as a paraoxybenzoic acid ester, sodium benzoate, salicylic acid, sorbic acid or boric acid; an antioxidant such as butylhydroxyanisole or dibutylhydroxytoluene; etc., may be added.
Further, in, order to stimulate percutaneous absorption in an ointment, an absorption promoter such as diisopropyl adipate, diethyl sebacate, ethyl caproate or ethyl laurate may be compounded. Also, for stabilization, a compound of the present invention may be used in the form of a clathrate compound prepared by using xcex1, xcex2 or xcex3-cyclodextrin, a methylated cyclodextrin, etc. An ointment can be prepared by a conventional process.
In the creams, dosage forms of oil-in-water type are preferable with the aim of stabilizing compounds of the present invention. Further, the above-mentioned fatty oil, higher alcohol, glycol, or the like may be used as the base of a cream, and diethylene glycol, propylene glycol, sorbitan mono fatty acid ester, polysorbate 80, sodium laurylsulfate, or the like may be used as the emulsifier of a cream. Further, the above-mentioned preservative, antioxidant, or the like may be added, as necessary. Furthermore, as in the case of ointment, a compound of the present invention can be used in the form of a clathrate compound prepared by using a cyclodextrin or a methylcyclodextrin. A cream can be prepared according to a conventional process.
Examples of the lotions include a suspension-type lotion, an emulsion-type lotion and a solution-type lotion. The suspension-type lotion is prepared by using a suspending agent such as sodium alginate, traganth or sodium carboxymethylcellulose, and optionally by adding an antioxidant, a preservative, etc.
The emulsion-type lotion is prepared according to a conventional process by using an emulsifier such as sorbitan mono fatty acid ester, polysorbate 80 or sodium laurylsulfate. A compound of the present invention can be dissolved in an alcohol such as ethanol, and optionally an antioxidant, a preservative, or the like is added.
Besides the above-mentioned dosage forms, pastas, poultices, aerosols, etc., may be cited. Pharmaceutical preparations having these dosage forms can be prepared according to conventional processes.
Pharmaceutical preparations for intranasal administration are supplied in the form of a liquid or powdery composition. As the base of the liquid preparation, water, saline, a phosphate buffer solution, an acetate buffer solution, or the like is used, and the liquid preparation may contain further a surfactant, an antioxidant, a stabilizer, a preservative and/or a thickener. As the base for the powdery preparation, a water-absorbent base is preferable. Examples of the water-absorbent base include polyacrylate salts such as sodium polyacrylate, potassium polyacrylate and ammonium polyacrylate; cellulose lower-alkyl ethers such as methylcellulose, hydroxyethylcellulose, hydroxypropyl-cellulose and sodium carboxymethylcellulose; and polyethylene glycol, polyvinyl pyrrolidone, amylose, pullulan, etc., which are easily soluble in water. Further, they include cellulose compounds such as crystalline cellulose, xcex1-cellulose and cross-linked sodium carboxymethylcellulose; starch compounds such as hydroxypropyl starch, carboxymethyl starch, cross-linked starches, amylose, amylopectin and pectin; proteins such as gelatin, casein and sodium caseinate; gums such as gum arabic, tragacanth gum and glucomannan; and polyvinylpolypyrrolidone, cross-linked polyacrylic acid and salts thereof, cross-linked polyvinyl alcohols, etc., which are scarcely soluble in water. These compounds may be used alone or in mixtures of two or more thereof. The powdery preparation may be further compounded with an antioxidant, a coloring agent, a preservative, a disinfectant, an antiseptic, etc. These liquid and powdery preparations can be applied, for example, by using a spraying device, etc.
For intrarectal administration, ordinary suppositories such as gelatin soft capsule are used.
Further, for inhalation, a powdery or liquid composition prepared by using an active ingredient of a vitamin D3 derivative of the present invention alone or in combination with, an adequate biocompatible vehicle can be administered to disease sites using an applicator such as a spraying device, a nebulizer or an atomizer. Alternatively, an active ingredient may be administered to disease sites by using a pMDI (volumetric sprayer) in which a suspension or solution prepared by suspending or dissolving the active ingredient in a spraying agent for aerosol such as alternative flon is filled. Furthermore, the ingredient is dissolved in an ethanol aqueous solution, the solution is filled in an adequate sprayer, and thus, it can be administered to disease sites.
A pharmaceutically effective dose of an active ingredient of the present invention depends on administration route, age and sex of the patient and the conditions of the disease, but it is ordinarily about 0.001-100 xcexcg per day, preferably about 0.01-50 xcexcg per day, and administration frequency is ordinarily 1-3 time per day. The pharmaceutical preparation is preferably prepared , so as to meet these conditions.
Further, treating agents of the present invention for various kinds of diseases can be administered in combination with conventional medicines.
Effectiveness for inflammatory respiratory diseases of vitamin D3 derivatives expressed by the above formula (1) of the present invention has been demonstrated by experiments using lipopolysaccharide(LPS)-induced pneumonia hamsters, which are widely used as an inflammatory pulmonary disease model, as shown concretely in the below-mentioned examples. That is, it has been found that compounds of the present invention significantly suppress LPS-induced pneumonia by intra-respiratory tract administration or oral administration.
Effectiveness of vitamin D3 derivatives expressed by the above formula (1) of the present invention for diseases attributable to the vitamin D3 overactivity has been demonstrated based on the parameter of differentiation-inducing effect on HL-60 cells, as concretely shown in the below-mentioned examples. That is, the compound of the present invention specifically suppresses the differentiation of HL-60 cells induced by an active vitamin D3 (1xcex1, 25-dihydroxyvitamin D3), and accordingly it becomes clear that the compound of the present invention acts as an antagonist to vitamin D3. Other vitamin D3 derivatives expressed by the above formula (1) and having antagonistic effect to vitamin D3 also can be screened by a similar evaluation system to that used in experimental examples.
On the other hand, it has been clarified that the blood calcium level-elevation effects of compounds of the present invention is extremely reduced compared with that of 1xcex1, 25-dihydroxyvitamin D3 although the generally most worried side effect of active vitamin D3 compounds is the elevation of calcium level in blood. For example, the blood calcium level-elevation effects of compounds of the present invention in oral administration to rats, which are compared with that of 1xcex1, 25-dihydroxyvitamin D3, are as shown below:
Compound No. 3105c; 1/ greater than 100
Compound No. 3405, 1/ greater than 100
Compound No. 5102, 1/259
Compound No. 5107, 1/11.
From the above results, it is thought that in vitamin D3 derivatives expressed by the above formula (1), the separation of the development concentrations for anti-inflammatory effect and antagonistic effect to vitamin D3 from that for blood calcium level elevation effect has been achieved, and side effect will not be generated.
Thus, treating agents containing vitamin D3 derivatives expressed by the above formula (1) as active ingredients can be considered to be effective for inflammatory respiratory diseases or diseases attributable to the overactivity of vitamin D3.
By the way, it has been reported that an active vitamin D3 has various effects on cell metabolism. Examples of such reports include the stimulation of maturation and differentiation of cell (Tanaka, et al., Biochem. J., 204, 713-719 (1982); Amento, et al., J. Clin. Invest., 73, 731-739 (1984); Colston, et al., Endocrinology, 108, 1083-1086 (1981); Abeetl, et al., Proc. Natl. Acad. Sci., 78, 4990-4994 (1981)) and immunosuppression effect such as interleukin-2 production inhibition (Rigbi, Immunology Today, 9, 54-58 (1988)). In addition, also immunology synergistic effect has been detected, and the stimulation of the production of bactericidal oxygen metabolites and the stimulation of leukocyte chemotactic response have been discovered.
It has been recognized that also vitamin D3 derivatives expressed by the above formula (1) have the cell differentiation-inducing effect as mentioned above. This fact demonstrates that vitamin D3 derivatives expressed by the above formula (1) have possibilities of therapies in various fields including, for example, malignant tumor, psoriasis, rheumatoid arthritis, inflammatory diseases such as dermatitis and autoimmune diseases, and other If therapies associated with supplementary agents in chemotherapy of infectious diseases (especially, bacterial, viral or fungus) and other therapies associated with mononuclear phagocyte.
Further, it is expected that vitamin D3 derivatives expressed by the above formula (1) are also effective for the treatment of hypertension, the treatment of diabetes mellitus, the stimulation of hair growth and the treatment of acne, for which an active vitamin D3 is effective as shown by the following reports: the treatment of hypertension (Lind, et al., Acta Med. Scand., 222, 423-427 (1987)), the treatment of diabetes mellitus (Inomata, et al., Bone Mineral, 1, 187-192 (1986)), the stimulation of hair growth (Lancet, March 4, 478 (1989)) and the treatment of acne (Malloy, et al., Tricontinental Meeting for Investigative Dermatology, Washington, 1989).
Some of vitamin D3 derivatives of the present invention expressed by the above formula (1) are very high in bonding capacity to 1xcex1,25-dihydroxyvitamin D3 receptor, i.e. they have bonding capacities ranging from same degree to about {fraction (1/50)} of 1xcex1, 25-dihydroxyvitamin D3, and high vitamin D3-like effects can be expected. In other words, compounds of the present invention are expected to be effective as an osteoporosis treating agent based on bon,e metabolism maintaining effect characteristic to an active vitamin D3.